title: TRPC4 inactivation confers a survival benefit in severe pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure with lumen-occluding neointimal and plexiform lesions. Activation of store-operated calcium entry channels promotes contraction and proliferation of lung vascular cells. TRPC4 is a ubiquitously expressed store-operated calcium entry channel, but its role in PAH is unknown. We tested the hypothesis that TRPC4 promotes pulmonary arterial constriction and occlusive remodeling, leading to right ventricular failure in severe PAH. Severe PAH was induced in Sprague-Dawley rats and in wild-type and TRPC4-knockout Fischer 344 rats by a single subcutaneous injection of SU5416 [SU (semaxanib)], followed by hypoxia exposure (Hx; 10% O2) for 3 weeks and then a return to normoxia (Nx; 21% O2) for 3 to 10 additional weeks (SU/Hx/Nx). Although rats of both backgrounds exhibited indistinguishable pulmonary hypertensive responses to SU/Hx/Nx, Fischer 344 rats died within 6 to 8 weeks. Normoxic and hypertensive TRPC4-knockout rats recorded hemodynamic parameters similar to those of their wild-type littermates. However, TRPC4 inactivation conferred a striking survival benefit, due in part to preservation of cardiac output. Histological grading of vascular lesions revealed a reduction in the density of severely occluded small pulmonary arteries and in the number of plexiform lesions in TRPC4-knockout rats. TRPC4 inactivation therefore provides a survival benefit in severe PAH, associated with a decrease in the magnitude of occlusive remodeling.
authors.affiliation: Department of Pharmacology, Jordan University of Science and Technology, Irbid, Jordan; Department of Pharmacology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Alzoubi
authors.affiliation: Department of Internal Medicine, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama.
authors.forename: Philip
authors.initials: P
authors.lastname: Almalouf
authors.affiliation: Center for Lung Biology, University of South Alabama, Mobile, Alabama; Department of Respiratory Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Michie
authors.initials: M
authors.lastname: Toba
authors.affiliation: Department of Pharmacology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama.
authors.forename: Kealan
authors.initials: K
authors.lastname: O'Neill
authors.affiliation: Department of Physiology, University of South Alabama, Mobile, Alabama.
authors.forename: Xun
authors.initials: X
authors.lastname: Qian
authors.affiliation: Department of Physiology, University of South Alabama, Mobile, Alabama.
authors.forename: Michael
authors.initials: M
authors.lastname: Francis
authors.affiliation: Department of Physiology, University of South Alabama, Mobile, Alabama.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Taylor
authors.affiliation: Center for Lung Biology, University of South Alabama, Mobile, Alabama; Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Alexeyev
authors.affiliation: Department of Pharmacology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama; Department of Internal Medicine, University of South Alabama, Mobile, Alabama.
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
authors.affiliation: Department of Pharmacology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama; Department of Internal Medicine, University of South Alabama, Mobile, Alabama.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
authors.affiliation: Department of Pharmacology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama; Department of Internal Medicine, University of South Alabama, Mobile, Alabama. Electronic address: tstevens@southalabama.edu.
authors.forename: Troy
authors.initials: T
authors.lastname: Stevens
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D002302:Cardiac Output / Q000187:drug effects; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000009:adverse effects / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; C116890:Semaxinib